To date, a variety of beta-lactam drugs have been developed and beta-lactam drugs have become clinically extremely important antimicrobial drugs. However, there are increasing number of bacterial types which have obtained resistancy against beta-lactam drugs by producing beta-lactamase, which degrade beta-lactam drugs. According to the Ambler molecular classification, beta-lactamase are largely classified into four classes. Specifically, those are Class A (TEM type, SHV type, CTX-M type and the like), Class B (IMP type, VIM type, L-1 type and the like), Class C (AmpC type) and Class D (OXA type and the like). Amongst these, Classes A, C and D types are largely classified into serine-beta-lactamase, and on the other hand, Class B type is classified into metallo-beta-lactamase. It has been known that both have respectively different mechanisms to each other in terms of hydrolysis of beta-lactam drugs.
Recently, clinical problem has been occurring due to the existence of Gram negative bacteria which have become highly resistant to beta-lactam drugs including Cephems and Carbapenems by production of Class A (ESBL) or D types serine-beta-lactamase and Class B type metallo-beta-lactamase which have extended their substrate spectrum. Particularly, metallo-beta-lactamase is known to be one of the causes of obtaining multi-resistancy in Gram negative bacteria. Cephem compounds which exhibit intermediate activity against metallo-beta-lactamase producing Gram negative bacteria are known (e.g., Patent Document 1 and Non-Patent Document 1). However, there is a demand for development of Cephem compounds which exhibit more potent antimicrobial activity, in particular effectivity against a variety of beta-lactamase producing Gram negative bacteria.
One of the known antimicrobials having high anti-Gram negative bactericidal activity is Cephem compounds having a catechol group intramolecularly (e.g., Non-Patent Documents 2-4). The action thereof is that the catechol group forms a chelate with Fe3+, thereby the compound is efficiently incorporated into the bacterial body by means of Fe3+ transportation system on the cellular membrane (tonB-dependent iron transport system). Therefore, research has been conducted on compounds having catechol or similar structure thereto, on the 3-side chain or 7-side chain on the Cephem backbone.
Patent Documents 8 and Non-patent Documents 2-11 and 16 disclose compounds having a catechol or a structure similar thereto on the 3-side chain of the Cephem backbone.
Patent Document 9 and Non-patent Documents 12-15 disclose compounds having a catechol or a structure similar thereto on the 7-side chain of the Cephem backbone.
Non-patent Documents 7, 9, 10 and 12-15 describe Cephem compounds which have been stabilized against beta-lactamase.
However, these references do not disclose the compounds of the subject invention. Furthermore, these references, which describe Cephem compounds having catechol group intramolecularly, have no specific description regarding metallo-beta-lactamase of Class B type, or antibacterial activity against wide spectrum of Gram negative bacteria including Class B type.
Patent Documents 10 and 11 do not specifically disclose Cephem compounds having catechol type substituents. However, the present applicant filed a patent application for Cephem compounds having catechol type substituents (Patent Document 12).